In recent years, calcineurin inhibitors such as cyclosporine and FK506 are used to suppress rejection of patients who underwent organ transplantation. However, a certain kind of calcineurin inhibitor such as cyclosporine sometimes causes adverse side effects such as renal toxicity, liver toxicity, neurotoxicity and the like. Therefore, the development of a safer and highly effective pharmaceutical agent is ongoing to suppress rejection of transplant patients.
Patent references 1-3 disclose 2-aminopropane-1,3-diol compounds are useful as suppressants of (acute or chronic) rejection in organ or bone marrow transplantation, as well as therapeutic drugs for various autoimmune diseases such as psoriasis, Behcet's disease and the like and rheumatism diseases.
One of these compounds, 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (hereinafter to be sometimes referred to as FTY720) is currently under clinical development as a suppressant of rejection in renal transplantation. FTY720 is rapidly converted to phospho-FTY720 (hereinafter to be sometimes referred to as FTY720-P, e.g., 2-amino-2-phosphoryloxymethyl-4-(4-octylphenyl)butanol) by sphingosine kinase in vivo. FTY720-P acts as an agonist of 4 kinds of S1P receptors (other than S1P2) out of 5 kinds of sphingosine-1-phosphate (hereinafter to be sometimes referred to as S1P) receptors (hereinafter to be sometimes referred to as S1P1-5, respectively) (non-patent reference 1).
Recently, it has been suggested that S1P1 in S1P receptors is essential for the emigration of mature lymphocytes from thymus and secondary lymphoid tissues. FTY720-P acts as an S1P1 agonist to down-regulate S1P1 on lymphocytes. As a result, the emigration of mature lymphocytes from thymus and secondary lymphoid tissues is inhibited and circulating mature lymphocytes in blood are sequestered in the secondary lymphoid tissues, whereby the immunosuppressive action is exhibited (non-patent reference 2).
On the other hand, conventional 2-aminopropane-1,3-diol compounds are feared to show transient bradycardia expression as side effects, and to solve this problem, a number of novel compounds obtained by modifying the chemical structures of 2-aminopropane-1,3-diol compounds have been reported. Among those, as a compound having a substituent on the benzene ring of FTY720, patent reference 4 discloses an aminopropanol derivative as an S1P receptor modulator with a phosphoric group, and patent references 5 and 6 both disclose aminopropanol derivatives as S1P receptor modulators. However, a trihaloalkyl group, for example, a trifluoromethyl group, is not disclosed as a substituent on the benzene ring therein. In effect, the level of safety as a pharmaceutical product has not reached a satisfactory level as the situation stands.    patent reference 1: WO94/08943    patent reference 2: WO96/06068    patent reference 3: WO98/45429    patent reference 4: WO02/076995    patent reference 5: WO2004/096752    patent reference 6: WO2004/110979    non-patent reference 1: Science, 2002, vol. 296, pages 346-349    non-patent reference 2: Nature, 2004, vol. 427, pages 355-360